Controlled release matrix for pharmaceuticals

ABSTRACT

The controlled release of therapeutically active agents is achieved from a controlled release matrix of sodium alginate and a calcium salt. When the composition is to be administered rectally, the matrix is combined with a therapeutically active agent and a suitable suppository base. When the composition is to be administered orally, the matrix further includes a higher aliphatic alcohol.

This is a continuation of application(s) Ser. No. 08/017,017 filed onFeb. 12, 1993, now abandoned which, in turn, is a divisional of Ser. No.07/758,883, filed Sep. 11, 1991, now U.S. Pat. No. 5,215,758.

Sustained release dosage forms are central in the search for improvedtherapy, both through improved patient compliance and decreasedincidences of adverse drug reactions. Ideally, a controlled releasedosage form will provide therapeutic concentration of the drug in bloodthat is maintained throughout the dosing interval with a reduction inthe peak/nadir concentration ratio. Central to the development processare the many variables that influence the in-vivo release and subsequentabsorption of the active ingredients from the gastrointestinal tract.

Controlled release formulations known in the art include speciallycoated beads or pellets, coated tablets and ion exchange resins, whereinthe slow release of the active drug is brought about through selectivebreakdown of the coating of the preparation or through formulation witha special matrix to affect the release of the drug. Some controlledrelease formulations provide for sequential release of a single dose ofan active medicament at predetermined periods after administration.

It is the aim of all controlled release preparations to provide a longerduration of pharmacological response after the administration of thedosage form than is ordinarily experienced after the administration ofan immediate release dosage form. Such extended periods of responseprovides for many inherent therapeutic benefits that are not achievedwith short acting, immediate release products. Thus, therapy may becontinued without interrupting the sleep of the patient, which is ofspecial importance when treating an epileptic patient to preventnocturnal seizures, or patients with pain who experience severe pain onawakening, as well as for debilitated patients for whom an uninterruptedsleep is essential.

Another critical role for extending the duration of action ofmedications is in therapy of cardiovascular diseases wherein optimalpeak blood levels of a medication must be maintained at steady statelevel in order to achieve the desired therapeutic effect. Unlessconventional immediate release dosage forms are carefully administeredat frequent intervals, peaks and valleys in the blood level of theactive drug occur because of the rapid absorption and systemic excretionof the compound and through metabolic inactivation, thereby producingspecial problems in maintenance therapy of the patient. A furthergeneral advantage of longer acting drug preparations is improved patientcompliance resulting from the avoidance of missed doses throughforgetfulness.

The prior art teaching of the preparation and use of compositionsproviding for controlled release of an active compound from a carrier isbasically concerned with the release of the active substance into thephysiologic fluid of the alimentary tract. However, it is generallyrecognized that the mere presence of an active substance in thegastrointestinal fluids does not, by itself, insure bioavailability.Bioavailability, in a more meaningful sense, is the degree, or amount,to which a drug substance is absorbed into the systemic circulation inorder to be available to a target tissue site.

To be absorbed, an active drug substance must be in solution. The timerequired for a given proportion of an active drug substance contained ina dosage unit to enter into solution inappropriate physiologic fluids isknown as the dissolution time. The dissolution time of an activesubstance from a dosage unit is determined as the proportion of theamount of active drug substance released from the dosage unit over aspecified time by a test method conducted under standardized conditions.The physiologic fluids of the gastrointestinal tract are the media fordetermining dissolution time. The present state of the art recognizesmany satisfactory test procedures to measure dissolution time forpharmaceutical compositions, and these test procedures are described inofficial compendia world wide.

Although there are many diverse factors which influence the dissolutionof a drug substance from its carrier, the dissolution time determinedfor a pharmacologically active substance from a specific composition isrelatively constant and reproducible. Among the different factorsaffecting the dissolution time are the surface area of the drugsubstance presented to the dissolution solvent medium, the pH of thesolution, the solubility of the substance in the specific solventmedium, and the driving forces of the saturation concentration ofdissolved materials in the solvent medium. Thus, the dissolutionconcentration of an active drug substance is dynamically modified inthis steady state as components are removed from the dissolution mediumthrough absorption across the tissue site. Under physiologicalconditions, the saturation level of the dissolved materials isreplenished from the dosage form reserve to maintain a relativelyuniform and constant dissolution concentration in the solvent medium,providing for a steady state absorption.

The transport across a tissue absorption site in the gastrointestinaltract is influenced by the Donnan osmotic equilibrium forces on bothsides of the membrane, since the direction of the driving force is thedifference between the concentrations of active substance on either sideof the membrane, i.e. the amount dissolved in the gastrointestinalfluids and the amount present in the blood. Since the blood levels areconstantly being modified by dilution, circulatory changes, tissuestorage, metabolic conversion and systemic excretion, the flow of activematerials is directed from the gastrointestinal tract into the bloodstream.

Notwithstanding the diverse factors influencing both dissolution andabsorption of a drug substance. A strong correlation has beenestablished between the in-vitro dissolution time determined for adosage form and the in-vivo bioavailability. this correlation is sofirmly established in the art that dissolution time has become generallydescriptive of bioavailability potential for the active component of theparticular dosage unit composition. In view of this relationship, it isclear that the dissolution time determined for a composition is one ofthe important fundamental characteristics for consideration whenevaluating controlled release compositions.

Certain controlled release pharmaceutical compositions for oraladministration consisting of a release matrix of sodium alginate andcalcium salts have been discussed in the art. For example, in vitroevaluations of floating alginate gel-systems consisting of sodiumalginate, calcium phosphate, sodium bicarbonate, drug and diluent filledin a gelatin capsule have been reported by Protan. Protan also reportsthat a method for treatment of diabetes by encapsulating islets ofLangerhans in calcium alginate beads coated with a semi-permeablemembrane have been developed.

However, less attention has been paid to the production of formulationswhere the route of administration is other than oral or where the activedrug is highly water soluble. In situations where a drug cannot be takenorally, or where the physical condition does not permit oraladministration, an alternate route of administration with a similarcontrolled release profile as the oral route is highly desirable.

In addition, improvements in the controlled release of therapeuticallyactive agents from matrices of calcium salts/sodium alginates are alsodesirable.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a new controlledrelease matrix which extends the time of release of active medicamentsincorporated therein.

It is another object of the present invention to provide controlledrelease matrix compositions which are useful for all types ofpharmaceutically active ingredients and which can extend the time ofrelease of all such ingredients.

It is yet another object of the present invention to provide acontrolled release matrix useful in rectal formulations.

In accordance with the above objects and other, the present invention isdirected to controlled release compositions for the controlled releaseof therapeutically active ingredients over a pre-determined period oftime, e.g. from five hours to as much as 24 hours after administrationin human or animals.

More particularly, the present invention is related to a controlledrelease pharmaceutical composition for rectal administration, comprisinga controlled release matrix comprising a pharmaceutically acceptablesodium alginate and a pharmaceutically acceptable calcium salt, atherapeutically active agent, and a suitable vehicle which melts ordissolves in rectal fluids. The calcium salt cross-links with the sodiumalginate when the vehicle dissolves or melts, or when the components areexposed to aqueous solutions. Thereby, the release of thetherapeutically active agent from the composition is controlled.

The present invention is also related to a controlled releasepharmaceutical composition for oral administration, comprising acontrolled release matrix comprising a pharmaceutically acceptablesodium alginate, a pharmaceutically acceptable calcium salt whichcross-links with the sodium alginate when the composition is exposed toaqueous solutions, an effective amount of a higher aliphatic alcohol,and an effective amount of an active agent distributed or suspended insaid controlled release matrix. The amount of higher aliphatic alcoholincluded is sufficient to obtain a desired rate of release of the activeagent. The higher aliphatic alcohol preferably contains from about 8 toabout 18 carbon atoms.

The present invention is further related to a controlled release matrixfor the release of an orally administered therapeutically active agent,comprising from about 10 to about 50 percent by weight of apharmaceutically acceptable sodium alginate, a sufficient amount of apharmaceutically acceptable calcium salt to cross-link with the sodiumalginate when the matrix is exposed to aqueous solutions or gastricfluid, and an effective amount of a higher aliphatic alcohol to obtain adesired rate of release of an active agent to be incorporated into thematrix.

The present invention is also related to a method for providing acontrolled release suppository containing a pharmaceutically activeagent, comprising combining a pharmaceutically acceptable sodiumalginate, a pharmaceutically acceptable calcium salt in an amounteffective to cross-link with the sodium alginate, and an effectiveamount of a therapeutically active agent, and then adding the mixture tosufficient quantity of a suitable melted vehicle. Suppositories are thenprepared by pouring the mixture into molds and cooling.

The present invention is further related to a method of providing anorally administered controlled release composition for a therapeuticallyactive agent, comprising preparing a controlled release matrix bycombining a pharmaceutically acceptable sodium alginate with apharmaceutically acceptable calcium salt capable of cross-linking thesodium alginate when exposed to aqueous solutions, a higher aliphaticalcohol, and an effective amount of a therapeutically active agent, suchthat the therapeutically active agent is suspended or distributed in thematrix, and including a sufficient amount of the calcium salt and higheraliphatic alcohol to control the release of said therapeutically activeagent from the matrix at a desired rate when the composition is exposedto aqueous solutions.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graphical representation of mean plasma concentrations ofmorphine sulphate taken over a 24 hour period.

DETAILED DESCRIPTION

An important aspect of the present invention is related in part to therealization that a controlled release matrix for the oral administrationof a wide variety of therapeutically active agents is obtained from thecombination of a pharmaceutically acceptable sodium alginate, apharmaceutically acceptable calcium salt, and a higher aliphaticalcohol.

Another important aspect of the present invention is directed to thediscovery that a controlled release composition for rectaladministration of a wide variety of drugs can be obtained from thecombination of a pharmaceutically acceptable sodium alginate, apharmaceutically acceptable calcium salt.

The bioavailability of rectally administered drugs is known to beerratic, and it is commonly the case that rectal absorption of a drugmay be substantially different from absorption following oraladministration.

Among the different factors affecting the dissolution time are thesurface area of the drug substance presented to the dissolution solventmedium, the pH of the solution, the solubility of the substance in thespecific solvent medium, and the driving forces of the saturationconcentration of dissolved materials in the solvent medium. In the caseof an orally administered drug, the physiologic fluids of thegastrointestinal tract are the media for determining dissolution time.Generally, factors affecting the absorption of drugs from suppositoriesadministered rectally include anorectal physiology, suppository vehicle,absorption site pH, drug pK_(a), degree of ionization, and lipidsolubility.

Any pharmaceutically acceptable sodium alginate may be used inconjunction with the present invention the most preferred having aviscosity range between 10-500 cps as a one percent solution in water.More preferably, the alginate is a sodium alginate having a viscosity offrom about 40 to about 150 cps as a one percent solution. In certainpreferred embodiments the alginate has a viscosity from about 40 toabout 70 cps as a one percent solution, for example when the matrix ofthe present invention is to be used in conjunction with a less solubledrug or when a faster dissolution profile is desired. In otherembodiments, the alginate has a viscosity from about 70 to about 150cps, for example when the drug to be incorporated is relatively watersoluble or when a slow dissolution rate is desired. In yet otherpreferred embodiments, the sodium alginate has a viscosity from about300 to about 500 cps as a one percent solution.

In terms of particle size, the sodium alginate preferably has a particlesize from about 45 to about 125 microns, more preferably has a particlesize of 70 microns or less.

Any alginates which are pharmaceutically acceptable can be used for thepurposes of the present invention. Examples of commercially availablealginates suitable for use in conjunction with the present invention arethose that are marketed under the trade name "Protanal™" and "Keltone™",and are available from Protan A/S, Norway and Merck & Co. Inc., NewJersey, U.S.A. respectively.

The amount of alginate contained in the controlled release matrices andcompositions of the present invention is dependent upon many factors,including the desired duration of action and the nature of the activedrug substance to be incorporated into the composition. In general, theamount of alginate in the total composition is from about 10 to about 50percent by weight and in certain embodiments more preferably from about15 to about 30 percent by weight. The amount of alginate may be higheror lower depending upon the dosage regimen desired (once-a-day,twice-a-day, three-times-a-day, etc.).

Suitable calcium salts for use in the matrices and compositions of thepresent invention include calcium phosphate, dicalcium phosphate,calcium chloride, calcium carbonate, calcium acetate, and calciumgluconate. Other pharmaceutically acceptable calcium salts known in theart may also be used.

The amount of calcium salt in the compositions of the present inventionmust be sufficient to cross-link with the alginate when exposed tosolutions (e.g. gastric fluid in the case of oral preparations, themelted base and rectal fluids in the case of a rectal preparation) suchthat a gel matrix is formed from which the drug is slowly released.Generally, in terms of the amount of sodium alginate in the composition,the amount of calcium salt is from about 2 to about 12 percent, and morepreferably from about 8 to about 12 percent, by weight of the amount ofsodium alginate present in the composition. In terms of the composition,the amount of calcium is generally from about 1 to about 4 percent, byweight.

Although it is preferred that calcium salts be used in the presentinvention, salts of other multivalent ions may be used instead such asAl³⁺.

Generally, the controlled release compositions of the present inventionprovide sustained release of the drug(s) over a predetermined or aspecified period of time, e.g. over a period of time from about 4-5hours to as much as 24 hours after administration in humans or animals.

The controlled release compositions of the present invention for oraladministration comprise a sodium alginate, a calcium salt and a higheraliphatic alcohol containing from 8 to 18 carbon atoms, which isoptionally substituted by a further aliphatic group containing fromabout 8 to about 18 carbon atoms. The controlled release compositions ofthe present invention may be administered orally in the form of tablets,capsules, etc. It is also contemplated that the compositions of thepresent invention may be adapted for buccal administration.

Examples of suitable higher aliphatic alcohols include fatty alcoholssuch as lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcoholand cetostearyl alcohol, and mixtures thereof.

The level of higher aliphatic alcohol in the oral compositions of thepresent invention is determined by the rate of drug release required.Generally, the compositions will contain from about 5% to about 45%(w/w), and preferably from about 10% to about 30% (w/w), of the higheraliphatic alcohol, as a proportion to the weight of the composition. Thegreater the amount of higher aliphatic alcohol included in the matrix,the slower the rate of release of the drug.

Upon oral ingestion and contact with fluids, the compositions of thepresent invention swell and gel to form a matrix from which the drug isreleased. Since the drug is suspended or distributed throughout thecomposition (and consequently throughout the matrix), a constant amountof drug can be released per unit time in vivo by dispersion or erosionof the outer portions of the matrix.

Any pharmaceutically accepted soluble or insoluble inert pharmaceuticalfiller (diluent) material can be used in the compositions of the presentinvention, such as monosaccharides, disaccharides, polyhydric alcohols,or mixtures thereof. Examples of inert diluents include sucrose,dextrose, lactose, microcrystalline cellulose, xylitol, fructose,sorbitol, mixtures thereof and the like. However, it is preferred that asoluble pharmaceutical filler such as lactose, dextrose, sucrose, ormixtures thereof be used.

In the case of tablets, an effective amount of any generally acceptedpharmaceutical lubricant, including the calcium or magnesium soaps maybe added to the above-mentioned ingredients of the excipient be added atthe time the medicament is added, or in any event prior to compressioninto a solid dosage form. Most preferred is magnesium stearate in anamount of about 0.5-3% by weight of the solid dosage form.

In preparing the matrices of the present invention for oraladministration, the sodium alginate, calcium salt, drug(s) and higheraliphatic alcohol can be combined together using a wet granulationtechnique of at least one step, to form a uniform granulate togetherwith any of the other excipients that are required for the tableting orthe capsule filling. Alternatively, the drug(s) can be combined duringthe process of preparing the granulate, or mixed with the granulateafter it is prepared.

The moist granulated mass with or without the drug(s) is then dried andthen the granulate is sized using a suitable screening device, whichthen provides a flowable powder which can then be filled into capsulesor compressed into matrix tablets or caplets.

The controlled release matrix for rectal administration comprises sodiumalginate and a calcium salt. The composition for rectal administrationfurther comprises a drug and a suitable suppository vehicle (base). Thesuppository base chosen should of course be compatible with the drug(s)to be incorporated into the composition. Further, the suppository baseis preferably nontoxic and nonirritating to mucous membranes, melts ordissolves in rectal fluids, and is stable during storage.

Prior to absorption, the drug must be in solution. In the case ofsuppositories, solution must be preceded by dissolution of the base, orthe melting of the base and subsequent partition of the drug from thebase into the rectal fluid.

The bioavailability of the drug can be altered by the suppository base.Thus, the particular base to be used in conjunction with a particulardrug must be chosen giving consideration to the physical properties ofthe drug. For example, lipid-soluble drugs will not partition readilyinto the rectal fluid, but drugs that are only slightly soluble in thelipid base will partition readily into the rectal fluid.

In certain preferred embodiments of the present invention for bothwater-soluble and water-insoluble drugs, the suppository base comprisesa fatty acid wax selected from the group consisting of mono-, di- andtriglycerides of saturated, natural fatty acids of the chain length C₁₂to C₁₈.

In preparing the suppositories of the present invention other excipientsmay be used. For example, a wax may be used to suspend the alginate andcalcium salt, as well as to form the proper shape for administration viathe rectal route.

This system can also be used without wax, but with the addition ofdiluent filled in a gelatin capsule for both rectal and oraladministration.

Examples of suitable commercially available mono-, di- and triglyceridesinclude saturated natural fatty acids of the 12-18 carbon atom chainsold under the trade name Novata™ (types AB, AB, B,BC, BD, BBC, E, BCF,C, D and 299), manufactured by Henkel, and Witepsol™ (types H5, H12,H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58,E75, E76 and E85), manufactured by Dynamit Nobel.

Other pharmaceutically acceptable suppository bases may be substitutedin whole or in part for the above-mentioned mono-, di- andtriglycerides. The amount of base in the suppository is determined bythe size (i.e. actual weight) of the dosage form, the amount of alginateand drug used. Generally, the amount of suppository base is from about20 percent to about 90 percent by weight of the total weight of thesuppository. Preferably, the amount of base in the suppository is fromabout 65 percent to about 80 percent, by weight of the total weight ofthe suppository.

In preparing the matrices of the present invention for rectaladministration, the sodium alginate and calcium salt may be combinedtogether with the drug. Thereafter, the suppository base can be melted,and the mixed powder added to the melted base and mixed. The uniformmixture is then poured into suppository shells, and the suppositoriescooled.

The therapeutically active agents which may be used in the compositionsof the present invention include a wide variety of drugs, including bothwater-soluble and water-insoluble drugs.

Examples of different classes of therapeutically active pharmaceuticalagents that can be incorporated into the matrices of the presentinvention include antihistamines (e.g., dimenhydrinate, diphenhydramine(50-100 mg), chlorpheniramine and dexchlorpheniramine maleate),analgesics (e.g., aspirin, codeine, morphine (15-300 mg),dihydromorphone, oxycodone, etc.), anti-inflammatory agents (e.g.,naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen, aspirin,sulindac), gastro-intestinals and anti-emetics (e.g., metoclopramide(25-100 mg)), anti-epileptics (e.g., phenytoin, meprobamate andnitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem andnicardirine), anti-tussive agents and expectorants (e.g., codeinephosphate), anti-asthmatics (e.g. theophylline), anti-spasmodics (e.g.atropine, scopolamine), hormones (e.g., insulin, leparin), diuretics(e.g., eltacrymic acid, bendrofluazide), anti-hypotensives (e.g.,propranolol, clonidine), bronchodilators (e.g., albuterol),anti-inflammatory steroids (e.g., hydrocortisone, triamcinolone,prednisone), antibiotics (e.g., tetracycline), antihemorrhoidals,hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives,decongestants, laxatives, antacids, vitamins, stimulants (includingapetite suppressants such as phenylpropanolamine). The above list is notmeant to be exclusive.

DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples are given to further illustrate the presentinvention. The scope of the invention is not, however, meant to belimited to the specific details of the examples.

EXAMPLES 1-3

Morphine was tested in the controlled release system of the invention.The following three suppository formulations set forth in Table 1demonstrate the principle of the invention with reg2ard to a controlledrelease morphine suppository containing 30 mg active ingredient, theapplicability and the advantages for pharmaceutical use.

                  TABLE 1                                                         ______________________________________                                        Morphine Suppository Formulations                                                            EXAMPLE                                                        INGREDIENT     1         2         3                                          ______________________________________                                        Morphine Sulphate .5H.sub.2 O                                                                30.0 mg   30.0 mg   30.0 mg                                    Sodium Alginate                                                                              327.5 mg  409.5 mg  450.0 mg                                   (low viscosity LF grade)                                                      DiCalcium phosphate                                                                          32.5 mg   40.5 mg   45.0 mg                                    Novata-B       1410.0 mg 1320.0 mg 1275.0 mg                                  Total          1800.0 mg 1800.0 mg 1800.0 mg                                  ______________________________________                                    

Novata-B is a mixture of mono-, di- and triglycerides based on saturatednatural fatty acids of the chain lengths C₁₂ to C₁₈, with a specificmelting range (33.4° C.-25.5° C.).

The suppositories were prepared according to the following method:morphine sulphate powder, sodium alginate and calcium phosphate were allpassed through a #200 sieve, individually. All three powders wereintimately mixed in a suitable mixing apparatus. Novata B was melted ina stainless steel pot, keeping the temperature below 60° C.

The mixed powder was then added to the completely melted wax (around 50°C.) with constant stirring. The temperature was then cooled slowly to40° C. and kept constant at that temperature. The uniform suspension wasthen transferred to a automated suppository filing kettle, andcontinuously stirred at 38° C.

After the fill weight was determined, the suppository shells were filledto the suggested fill weight at a temperature of about 37° C. (e.g.,between 36°-38° C.). The suppositories were allowed to cool, thensealed.

Dissolution results were then conducted using USP basket method, 50 rpm,in phosphate buffer at pH 6.8. The results are set forth in Table 2.

                  TABLE 2                                                         ______________________________________                                        PERCENT MORPHINE SULPHATE DISSOLVED                                           Hour  Formulation A                                                                              Formulation B                                                                              Formulation C                                 ______________________________________                                        1     35.0         21.7         21.8                                          2     49.5         45.5         30.2                                          3     74.4         50.6         42.4                                          4     89.5         63.4         45.7                                          6     100.0        80.1         60.6                                          8     --           90.5         70.1                                          10    --           100.0        83.0                                          12    --           --           92.7                                          ______________________________________                                    

In Example 1, the amount of alginate was about 18.2% the amount ofcalcium salt was about 1.81%, and the amount of glyceride was about 78%,by weight of the composition

In Example 2, the amount of alginate was about 22.75% the amount ofcalcium slat was about 2.25% and the amount of glyceride was about73.33% by weight of the composition. In Example 3, the amount ofalginate was about 25%, the amount of calcium salt was about 2.5%, andthe amount of glyceride was about 70.83%, by weight of the composition.

From the above dissolution results, as it can been seen that byincreasing the proportions of sodium alginate and calcium phosphate, therelease of morphine sulphate can be extended, e.g. to 6 to 12 hours.

EXAMPLES 4 and 5 Effect of Different Alginates

The usefulness of the invention was further demonstrated by thepreparation of morphine suppositories using different viscosity grade ofalginates.

The following two formulations set forth in Table 3 were prepared usingthe same method described for Examples 1-3. Each composition included22.5% alginate, 2.25% calcium salt, and 73.33% glyceride.

                  TABLE 3                                                         ______________________________________                                        Ingredient        Example 4  Example 5                                        ______________________________________                                        Morphine Sulphate .5H.sub.2 O                                                                   30.0 mg    30.0 mg                                          Protanal LF (Low Viscosity)                                                                     405.0 mg   --                                               Protanal SF (High Viscosity)                                                                    --         405.0 mg                                         Calcium Phosphate Dibasic                                                                       45.0 mg    45.0 mg                                          Novata B          1320.0 mg  1320.  mg                                        Total Weight      1800.0 mg  1800.0 mg                                        ______________________________________                                    

Dissolution results the results are set forth in for Examples 4 and 5were then obtained using the U.S.P. basket method 50 rpm, in pH 6.8Phosphate buffer.

                  TABLE 4                                                         ______________________________________                                        Percent Morphine Sulphate Dissolved                                           Hour         Example 4 Example 5                                              ______________________________________                                        1            19.3      15.6                                                   2            32.8      25.1                                                   3            45.8      37.0                                                   4            57.8      43.0                                                   6            78.7      64.9                                                   8            88.0      71.2                                                   ______________________________________                                    

When comparing the dissolution results of suppositories A and B, it wasobserved that by using a high viscosity alginate, the release profilewas sustained for a significantly longer period of time.

EXAMPLES 6-8 Varying amount of Drug

In Examples 6-8, controlled release suppositories of morphine sulphatewere prepared in which the amount of drug is 30 mg, 60 mg and 100 mg,respectively. The following suppository formulations set forth in Table5 (using the method described under Examples 1-3 above) were prepared.

                  TABLE 5                                                         ______________________________________                                        Ingredient     Example 6 Example 7 Example 8                                  ______________________________________                                        Morphine Sulphate .5H O                                                                      30 mg     60 mg     100 mg                                     Protanal SF 200                                                                              405 mg    360 mg    360 mg                                     Calcium Phosphate                                                                            45 mg     36 mg     36 mg                                      Dibasic                                                                       Novata B       1320 mg   1344 mg   1304 mg                                    Total          1800 mg   1800 mg   1800 mg                                    ______________________________________                                    

In Example 6, the composition included 22.5% alginate, 2.25% calciumsalt, and 73.33% glyceride.

In Example 7, the composition included 20% alginate, 2% calcium salt,and 74.66% glyceride.

In Example 8, the composition included 20% alginate, 2% calcium salt,and 72.44% glyceride.

The suppositories of Examples 6-8 were then tested for dissolution usingthe USP basket method, 50 rpm, in pH 6.8 Phosphate buffer for 8 hours.The dissolution results are set forth in Table 6 below.

                  TABLE 6                                                         ______________________________________                                        PERCENT MORPHINE SULPHATE DISSOLVED                                           Hour   Example 6     Example 7 Example 8                                      ______________________________________                                        1      14.45         17.15     16.58                                          2      22.57         30.68     25.43                                          3      33.00         40.36     35.80                                          4      43.56         48.85     42.81                                          6      57.23         65.08     56.35                                          8      65.88         69.67     68.55                                          ______________________________________                                    

Thus, different strengths of morphine suppositories with controlledrelease characteristics can be manufactured by varying the proportionsof the different ingredients in the controlled release system of thepresent invention.

EXAMPLES 9-11 ORAL CONTROLLED RELEASE SYSTEM

An oral controlled release composition according to the presentinvention was prepared with the formulation set forth in Table 7.

                  TABLE 7                                                         ______________________________________                                        Ingredient            Weight (mg)                                             ______________________________________                                        Dimenhydrinate         75                                                     Protanol SF/200        75                                                     (Sodium Alginate)                                                             Calcium Phosphate      7                                                      Lactose (spray dried)  25                                                     Cetostearyl Alcohol    30                                                     Magnesium Stearate     3                                                      Talc                   3                                                      Total                 218 mg                                                  ______________________________________                                    

The dimenhydrinate, protanol, calcium phosphate and lactose were dryblended until thoroughly mixed. Cetostearyl alcohol was added to thewarmed mixed powder, and the whole was mixed thoroughly. The mixture wasallowed to cool in the air, regranulated and sieved through a 16 meshscreen.

The coated granules were filled in a hard gelatin capsule using talc andmagnesium stearate as lubricants (capsules) or were compressed usingappropriate punches (tablets).

Dissolution studies of Example 9, using USP paddle method, 50 rpm werethen obtained in deionized water. Representative results for bothtablets and capsules are set forth in Table 8.

                  TABLE 8                                                         ______________________________________                                        Hour    Percent of Dimenhydrinate Dissolved                                   ______________________________________                                        1       15.00                                                                 2       29.00                                                                 3       47.00                                                                 4       70.00                                                                 5       77.00                                                                 6       91.00                                                                 ______________________________________                                    

In Example 10, the method of Example 9 was followed, except that theamount of cetostearyl alcohol was increased to 50 mg per capsule ortablet. Dissolution results of Example 10, using USP paddle method, 50rpm were then obtained in deionized water. Representative results forthe capsules and tablets are set forth in Table 9.

                  TABLE 9                                                         ______________________________________                                        Hour    Percent of Dimenhydrinate Dissolved                                   ______________________________________                                        1       25.00                                                                 2       34.00                                                                 3       38.00                                                                 4       53.00                                                                 6       71.00                                                                 ______________________________________                                    

In Example 11, the method of Example 9 was followed except the amount ofdimenhydrinate was decreased to 50 mg and the amount of lactoseincreased to 70 mg. Dissolution results of Example 11, using USP paddlemethod, 50 rpm were then obtained in deionized water. Representativeresults for the capsules and tablets are set forth in Table 10.

                  TABLE 10                                                        ______________________________________                                        Hour    Percent of Dimenhydrinate Dissolved                                   ______________________________________                                        1       22.00                                                                 2       47.00                                                                 3       82.00                                                                 4       92.00                                                                 6       100.00                                                                ______________________________________                                    

EXAMPLES 12-13 Bioavailability Comparison of Two Controlled ReleaseMorphine Rectal Suppository Formulations

A three-way crossover bioavailability study was conducted to compare two30 mg morphine sulfate controlled release rectal suppositories. Example12 was formulated according to Example 5 (high viscosity alginate) andExample 13 was formulated according to Example 4 (low viscosityalginate) with the marketed MS Contin 30 mg tablet given orally.

Fourteen (14) healthy male volunteers received single 30 mg doses ofeach of the two suppositories and MS Contin in randomized order,separated by a washout period of one week. In all phases, subjectsmaintained a reclining position for 1 hour and fasted for 4 hoursfollowing the dose. Preceding each rectal administration subjects wereadministered a Fleet enema and underwent proctoscopic examinationsbefore dosing and at the end of the blood sampling period. Blood sampleswere drawn prior to each dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,3.5, 4, 5, 6, 8, 10, 12, 16 and 24 hours after the dose. Plasma wasanalyzed by a RIA method using antibodies that did not crossreact withthe glucuronide metabolites. Mean plasma concentrations at each samplingtime are depicted graphically in FIG. 1.

Both suppositories produced excellent sustained release profiles. ForSuppositories A and B, maximum plasma concentrations (Cmax) were 7.8 and9.2 mg/ml respectively, compared to 10.4 mg/ml for MS contin. Curvewidth at half maximum plasma concentration (W₅₀) was approximately 10hours for both suppositories versus 4.3 hours for MS Contin. Overallbioavailability (AUC 0-24) was 39% greater than MS Contin for Example 12and 44% higher for Example 13. This increased bioavailability ispossibly the result of avoidance or reduction of the "first-pass"effect. Between-subject variability in bioavailability was greater forboth suppository formulations than for orally-administered MS Contintablets.

No serious or unexpected adverse reactions were noted for any of theformulations. Adverse experiences were reported in 2 subjects followingExample 12, in 6 subjects after Example 13, and in 4 subjects after MSContin (Table 2). The post-dose proctoscopic findings were limited tomild erythema in 6 subjects following Example 12 and 5 subjects afterExample 13 (for two of these latter subjects, mild erythema was alsoreported pre-dose).

Based on the foregoing results, either suppository would be suitableformulation. The effects of the difference in alginate viscosity betweenthe two suppository formulations appeared to be primarily limited toCmax, in that, for the high viscosity Example 12, Cmax was approximately85% of that observed with Example 13. Since side effects may have beenassociated with the higher peak concentration of Example 13 and, atsteady state, peak concentrations will be even higher, it is consideredthat the formulation with the lower Cmax (Example 12) may offer agreater margin of safety.

While the invention has been illustrated with respect to the foregoingexamples, different drugs, alginic acids, salts of multivalent ions andexcipients (including suppository bases) can be substituted. Suchvariations and modifications thereof can be made without departing fromthe spirit and scope of the invention, and are contemplated to be withinthe scope of the appended claims.

What is claimed is:
 1. A controlled release pharmaceutical compositionfor oral administration, comprisinga controlled release matrixconsisting essentially of a pharmaceutically acceptable sodium alginate,a pharmaceutically acceptable calcium salt which cross-links with thesodium alginate when said composition is exposed to aqueous solutions,and a higher aliphatic alcohol containing from about 8 to about 18carbon atoms, said sodium alginate comprising from about 10 to about 50percent by weight of said composition, and said calcium salt comprisingfrom about 2 to about 12 percent by weight of said sodium alginatepresent in said composition; and an effective amount of an active agentdistributed or suspended in said controlled release matrix, said higheraliphatic alcohol being in a predetermined amount to obtain a desiredrate of release of said active agent from said matrix when saidcomposition is exposed to aqueous solutions.
 2. The composition of claim1, wherein the sodium alginate is an amount from about 15 to about 30percent by weight of the composition.
 3. The composition of claim 1,wherein said calcium salt selected from the group consisting of calciumphosphate, dicalcium phosphate, calcium chloride, calcium carbonate,calcium acetate and calcium gluconate.
 4. The composition of claim 1,wherein said pharmaceutical agent is selected from the group consistingof amitriptyline, atropine, chlorpromazine, codeine, diclofenac,diphenhydramine, doxylamine, ephedrine, hyoscyamine, morphine,metoclopramide, hydromorphone, naproxyn, oxycodone, papaverine,phenylpropanolamine, propranolol, quinidine, scopolamine, theophyllineand thioridazine.
 5. The composition of claim 1, wherein saidcomposition is filled into a capsule.
 6. The composition of claim 1,wherein said composition is granulated and compressed into a tablet. 7.A controlled release matrix for the release of an orally administeredtherapeutically active agent, consisting essentially of from about 10 to50 percent by weight of a pharmaceutically acceptable sodium alginate, asufficient amount of a pharmaceutically acceptable calcium salt tocross-link with said sodium alginate when it is exposed to aqueoussolutions or gastric fluid and a predetermined amount of a higheraliphatic alcohol to obtain a desired rate of release of an active agentto be incorporated into said matrix, said higher aliphatic alcoholcontaining from about 8 to about 18 carbon atoms.
 8. A method ofproviding an orally administered controlled release composition for atherapeutically active agent, comprising preparing a controlled releasematrix consisting essentially of a pharmaceutically acceptable sodiumalginate, a pharmaceutically acceptable calcium salt capable ofcross-linking the sodium alginate when exposed to aqueous solutions, anda higher aliphatic alcohol containing from about 8 to about 18 carbonatoms, adding an effective amount of a therapeutically active agent tothe matrix such that said therapeutically active agent is suspended ordistributed in said matrix, and such that said sodium alginate comprisesfrom about 10 to about 50 percent by weight and said calcium saltcomprises from about 2 to about 12 percent by weight of said sodiumalginate present in said composition to control the release of saidtherapeutically active agent from said matrix at a desired rate whensaid composition is exposed to aqueous solutions.
 9. A controlledrelease pharmaceutical composition for oral administration,comprising:a) a controlled release matrix consisting essentially of:i) apharmaceutically acceptable sodium alginate; ii) a pharmaceuticallyacceptable calcium salt which cross-links with the sodium alginate whensaid composition is exposed to aqueous solutions; iii) a higheraliphatic alcohol containing from about 8 to about 18 carbon atoms; iv)an effective amount of an active agent distributed or suspended in saidcontrolled release matrix;said sodium alginate comprising from about 10to about 50 percent by weight of said composition, and said calcium saltcomprising from about 2 to about 12 percent by weight of said sodiumalginate present in said composition; and said higher aliphatic alcoholbeing in a predetermined amount to obtain a desired rate of release ofsaid active agent from said matrix when said composition is exposed toaqueous solutions; and b) one or more inert diluents.
 10. Thecomposition of claim 9, wherein said inert diluent is selected from thegroup consisting of monosaccharides, disaccharides, polyhydric alcoholsand mixtures thereof.
 11. A controlled release pharmaceuticalcomposition for oral administration, comprising a controlled releasematrix consisting essentially of:i) a pharmaceutically acceptable sodiumalginate; ii) a pharmaceutically acceptable calcium salt whichcross-links with the sodium alginate when said composition is exposed toaqueous solutions; iii) a higher aliphatic alcohol containing from about8 to about 18 carbon atoms; iv) an effective amount of an active agentdistributed or suspended in said controlled release matrix; and v) oneor more inert diluents;said sodium alginate comprising from about 10 toabout 50 percent by weight of said composition, and said calcium saltcomprising from about 2 to about 12 percent by weight of said sodiumalginate present in said composition; and said higher aliphatic alcoholbeing in a predetermined amount to obtain a desired rate of release ofsaid active agent from said matrix when said composition is exposed toaqueous solutions.
 12. The composition of claim 11, wherein said inertdiluent is selected from the group consisting of monosaccharides,disaccharides, polyhydric alcohols and mixtures thereof.